Obesity is a chronic disease and a major health concern in modern society. About 30% adults in U.S. are obese, and about 65% adults are overweight. Obesity is associated not only with a social stigma, but also with decreased life span and numerous health problems, including hypertension; type 2 diabetes mellitus; elevated plasma insulin concentrations; insulin resistance; dyslipidemia; hyperlipidemia; endometrial, breast, prostate and colon cancer; osteoarthritis; respiratory complications, such as obstructive sleep apnea; cholelithiasis; gallstones; arteriosclerosis; heart disease; abnormal heart rhythms; and heart arrhythmias. Kopelman, P. G., Nature 404, 635-643 (2000).
Existing therapies for obesity include standard diets and exercise, very low calorie diets, behavioral therapy, pharmacotherapy involving appetite suppressants, thermogenic drugs, food absorption inhibitors, mechanical devices such as jaw wiring, waist cords and balloons, and surgery. Jung and Chong, Clinical Endocrinology, 35: 11-20 (1991); Bray, Am. J. Clin. Nutr., 55: 538S-544S (1992). Protein-sparing modified fasting has been reported to be effective in weight reduction in adolescents. Lee et al., Clin. Pediatr., 31: 234-236 (April 1992). However, existing therapies are not very effective for a lot of obese patients. For the most severe obese patients, surgical intervention may be required. Considering the high prevalence of obesity in our society and the serious consequences associated therewith as discussed above, any therapeutic drug potentially useful in reducing weight of obese persons could have a profound beneficial effect on their health. There is a need for a drug that reduces total body weight of obese subjects toward their ideal body weight without significant adverse side effects and that helps the obese subject maintain the reduced weight level.
Neurotrophins are a family of small, homodimeric proteins, which play a crucial role in the development and maintenance of the nervous system. Members of the neurotrophin family include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), neurotrophin-6 (NT-6), and neurotrophin-7 (NT-7). Neurotrophins, similar to other polypeptide growth factors, affect their target cells through interactions with cell surface receptors. According to current knowledge, two kinds of transmembrane glycoprotein's serve as receptors for neurotrophins. Neurotrophin-responsive neurons possess a common low molecular weight (65-80 kDa), low affinity receptor (LNGFR), also known as p75NTR or p75, which binds NGF, BDNF, NT-3 and NT-4/5 with a KD of 2×10−9 M; and large molecular weight (130-150 kDa), high-affinity (KD in the 10−11 M range) receptors, which are members of the trk family of receptor tyrosine kinases. The identified members of the trk receptor family are trkA, trkB, and trkC.
Both BDNF and NT-4/5 bind to the trkB and p75NTR receptors with similar affinity. However, NT-4/5 and BDNF mutant mice exhibit quite contrasting phenotypes. Whereas NT-4/5−/− mice are viable and fertile with only a mild sensory deficit, BDNF−/− mice die during early postnatal stages with severe neuronal deficits and behavioral symptoms. Fan et al., Nat. Neurosci. 3(4):350-7, 2000; Liu et al., Nature 375:238-241, 1995; Conover et al., Nature 375:235-238, 1995; Ernfors et al., Nature 368:147-150, 1994; Jones et al., Cell 76:989-999, 1994. Several publications report that NT-4/5 and BDNF have distinct biological activities in vivo and suggest that the distinct activities may result partly from differential activation of the trkB receptor and its down-stream signaling pathways by NT-4/5 and BDNF. Fan et al., Nat. Neurosci. 3(4):350-7, 2000; Minichiello et al., Neuron. 21:335-45, 1998; Wirth et al., Development. 130(23):5827-38, 2003; Lopez et al., Program No. 38.6, 2003 Abstract, Society for Neuroscience.
It has been shown that BDNF and NT-4/5 have blood glucose and blood lipid controlling activity and anti-obesity activity in type II diabetic model animals, such as C57db/db mice. U.S. Pat. No. 6,391,312; Itakura et al., Metabolism 49:129-33 (2000); U.S. App. Pub. No. 2005/0209148; PCT WO 2005/082401. It has also been shown that BDNF has anti-obesity activity and activity of ameliorating leptin resistance in mice fed with high fat diet. U.S. Pub. No. 2003/0036512. Kernie et al. reported that BDNF or NT-4/5 could transiently reverse the eating behavior and obesity in heterozygous BDNF knock out mice in which BDNF gene expression was reduced. Kernie et al., EMBO J. 19(6):1290-300, 2000. It has been reported that a de novo missense mutation of Y722C substitution on human trkB results in impaired receptor phosphorylation and signaling to MAP kinase; and this mutation seems to result in a unique human syndrome of hyperphagic obesity. Yeo et al., Nat. Neurosci. 7:1187-1189 (2004).
Circulating levels of BDNF in people with obesity and in patients with anorexia nervosa have been studied. Monteleone et al., Psychosomatic Medicine 66:744-748, 2004; Nakazato et al., Biol. Psychiatry 54:485-490, 2003. Contrary to the prediction based on the findings that impairments of BDNF production in mice have been associated with increased food intake, reduced energy expenditure, and weight gain, circulating BDNF is significantly reduced in the anorexia nervosa patients and significantly increased in obese subjects as compared with the non-obese healthy controls. It has been hypothesized that in anorexia nervosa, BDNF reduction, by promoting food intake, attempts to counterbalance the patients' altered behaviors that lead to a negative balance; and in obesity, increased levels of BDNF may represent an adaptive mechanism to counteract the condition of positive energy imbalance by stimulating energy expenditure and decreasing food ingestion. Monteleone et al., Psychosomatic Medicine 66:744-748, 2004.
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